Peptides and proteins are essential components of organisms and have a variety of different functions. While proteins mainly have biocatalytical tasks (enzymes), as well as other related tasks they must perform in their capacity as important tissue components, peptides have important functions inside the organism, primarily as hormones, neurotransmitters and neuromodulators. By binding to membrane-bonded receptors, and the subsequent reactions in the cell physiology that are thereby mediated, peptides influence the communication from one cell to another cell and control a variety of vital processes, such as metabolism, immune response, digestion, respiration, pain sensation, reproduction, behavior, electrolyte balance, and more.
There exists therefore a need in the prior art to understand the precise relationships inside the organism, while providing, simultaneously, a necessary foundation for devising therapies in the treatment of pathogenic conditions. With the evolving discovery of the workings of biological processes on the molecular level, the interdisciplinary integration of biology and chemistry has evolved, supported by great advances in analytical processes and computer-supported theoretical methods. All of the above are important requirements for any successful identification of leads in the development of new active agents. Nevertheless, the road to the actual goal, which is the simple and efficient novel design of active agents, is still long-winding and remote. Typically, when working from natural structures as a starting point, comprehensive empirical research is required to synthesize libraries of possible target substances and optimize these agents for a certain activity. Moreover, aside from the high time requirement and cost expenditure, it is often found at a later time down the road that computer-developed active substances frequently exhibit the desired efficacy only inadequately in real and very complex biological systems (for example, in humans), or they have unacceptable side effects.
With this background in mind, the development, particularly also of peptidic and/or peptidemimetic active agents, is a great challenge, also in terms of the tasks that are involved in synthesizing them; in fact, in the context of the varied interdisciplinary interaction, it is ultimately the discipline of organic synthesis chemistry that determines what is feasible in terms of the possibilities and limitations for gaining access to the desired target molecules. Since, typically, these molecules must be constructed in as few steps as possible while still exhibiting stereoselectivity, new and better synthesis methodologies are always needed to meet this goal not only in the laboratory but down the road also in the context of large-scale applications. Structural mimetics of diproline units and the use thereof as a substituent in proline-riche peptides with PPII helix conformations are part of the prior art.
Some beta-turn peptide mimetics are known in the art as modulators of protein-protein interactions. WO 2006/067091 A1 discloses different peptides and peptide mimetics that prevent the homodimerization of MyD88 as well as the interaction between MyD88 and TIR. Beta-turn peptide mimetics are also known as modulators of protein-protein interactions between SH3 domains. For example, WO 98/54208 discloses that beta-turn peptide mimetics that include polyproline motifs and an alpha-helix structure are able to interact with SH3 domains. Witter et al (Bioorg. & Med. Chem. Let. 8 (1998) 3137) and Vartak et al (Organic Let. 2006, 8:5, 983) disclose different beta-turn peptide mimetics that can be used as mimetics for a polyproline sequence.
Known peptide mimetics, however, have a saturated central six-membered ring. Contrary to the prior art, the compounds according to the invention are characterized by an unsaturated central six-membered ring. The double bond in the central six-membered ring according to formula 1 of the present invention represents a considerable improvement in contrast to the prior art, due to increased stability of the compound and surprisingly improved affinity relative to target structures. All other known structures are of such a type so as to provide for the presence of a central 7-ring system that is connected to a side ring by two adjacent ring C atoms (WO 2008/040332 A1). The main advantage of the new scaffold lies in the fact that, due to the modified position of the vinylidene bridge, different steric demands emerge during the bonding step, contributing to considerable gains in terms of affinity, for example relative to EVH1 domains or, however, relative to other structures.